The long-term goal of the proposed PI, Dr. Yiqing Song, is to investigate the interrelationships among nutrient metabolisms, genetic variants, metabolic biomarkers, and risk of type 2 diabetes mellitus (DM) in epidemiologic studies. Through collaboration with his mentors at Brigham and Women's Hospital, the PI will develop expertise in all aspects of population genetic research needed for this project including genetic statistics and bioinformatics. Adequate intake of magnesium, an essential nutrient, is important in maintaining insulin and glucose homeostasis in the human body. There is also growing evidence, mostly from experimental studies, for a genetic basis of magnesium absorption and transport. This proposed research project will have two primary goals. First, this study will extend the applicant's previous epidemiologic research to examine the interrelationships between magnesium intake and biomarkers of systemic inflammation and lipid and lipoprotein metabolism in the Women's Health Study (WHS), a large prospective cohort with archived bio-specimens and detailed information on lifestyle factors and some biochemical markers. Second, the proposed genetic research will examine common genetic variants in seven genes involved in the magnesium homeostasis pathway in relation to the risk of type 2 DM in two prospective case-control studies nested in two large cohorts, the WHS (600 incident type 2 DM cases and 600 matched controls) and the Health Professionals Follow-up Study (HPFS) cohorts (1000 cases and 1000 matched controls). In addition to the primary goals, the proposed study will assess whether magnesium intake interacts with these genetic variants to modify risk of type 2 DM and will also apply several exploratory analytic approaches to explore the complex gene-gene and gene-environment interactions on type 2 DM risk. This proposal will enable the PI to develop the skills to launch his career as an independent investigator focusing on diabetes epidemiology. The proposed research project will provide a unique and comprehensive approach to better understand the mechanisms underlying the role of magnesium homeostasis in diabetes etiology, to help identify high-risk individuals, and to suggest new and more individualized treatment and/or prevention strategies.